Integrated approaches to understanding antipsychotic drug action at GPCRs

Abstract

The G-protein coupled receptor (GPCR) family of genes represents one of the largest druggable families of genes in the human genome. This is evident by the fact that approximately 30% of currently marketed drugs target GPCRs. However, many of these drugs are limited in their clinical potential as they are associated with debilitating side effects-a consequence of our incomplete understanding of their pharmacology and the signaling pathways regulated by GPCRs. Because of the limited range of tools available to resolve these issues, integrated approaches are required to fully understand the pharmacological action of drugs and the biochemical repertoire regulated by GPCRs. In this review we will focus on the action of antipsychotic drugs on certain monoamine GPCRs in the central nervous system (CNS) and the approaches being developed to elucidate their distinct pharmacology.

Figure 1

A) Schematic representation of antipsychotic (APS) action on G-protein (Gprot) and β-arrestin (βarr) signaling pathways and its effect on catalepsy and psychosis. Activation; inhibition/antagonist; partial agonist. Haloperidol (HAL) and aripiprazole (ARI) are used as representative typical and atypical APS, respectively. HAL and ARI act on D2 dopamine (D2R) and 5-HT2A serotonin receptors. Unlike HAL, ARI is a partial agonist at the D2-Gprot pathway and at 5-HT1A receptors, which might explain its non-cataleptic properties. Moreover, antagonist activity at the D2-βarr pathway and at 5-HT2A receptors might be largely responsible for reducing psychosis. B) Schematic representation of the various integrated approaches used to decipher antipsychotic action including novel techniques in development.